Safety versus Speed in Drug Development

The unstated tradeoff for drugmakers' increased investment in postapproval drug-safety monitoring is supposed to be greater US Food and Drug Administration flexibility in approving new drugs for market. In reality, the agency's burden of implementing a host of new drug-safety policies and programs has overtaxed staffers and slowed the new-drug review process. Outside criticism and internal dissent have heightened reviewers' fears about approving new products that raise safety concerns, thus exacerbating FDA's struggle to fulfill its many new statutory requirements and to meet review goals set by the Prescription Drug User Fee Act (PDUFA).

Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), acknowledges these challenges. Drugs are getting approved, but more slowly, she explained at the FDA Regulatory Symposium in September 2009. The problem is that the FDA Amendments Act of 2007 (FDAAA) added new requirements for assessing postmarketing studies and determining the need for Risk Evaluation and Mitigation Strategies (REMS) at the time of approval, but with no extension in review times. CDER has hired more staff and is implementing new procedures to make the review process more efficient. Electronic submission and review systems for drug applications would help, Woodcock noted. But these innovations remain far from reality, and many applications take much more than one review cycle to gain market approval.

As a result, the US may be falling behind Europe in approving innovative therapies for patients. At a meeting in September 2009 sponsored by the Institute of Medicine (IOM) to evaluate safety initiatives established by FDAAA, Peter Honig, executive vice-president of Merck (Whitehouse Station, NJ), noted that first-cycle approvals are down and that user-fee approval dates are "routinely missed" because of increased scrutiny of safety issues. FDA is "clearly struggling" with postmarket safety demands, he said, adding that "drug lag" may be rearing up once more as European regulators approve some new drugs for market faster than US regulators.

The approval slowdown is noticeably affecting drugs to which the agency has granted priority-review status, a designation traditionally reserved for the most innovative and important new therapies. In the past, about 70% of priority-review applications gained first-cycle approval, but this proportion dropped to 50% in 2008, according to a recent report from Parexel Consulting. User-fee approval targets are 10 months for new drug applications (NDAs) and six months for priority applications. It is particularly difficult for reviewers to accelerate the latter review goal.

The good news is that signs indicate a surge in NDAs filed with FDA and a more robust pipeline for new drugs. Parexel cited 147 NDAs pending at FDA at the beginning of 2009, a notable increase from the 86 under review one year earlier. The number of applications for new molecular entities (NMEs) appears to be holding steady, but the percentage enjoying first-cycle reviews has been dropping slightly, but steadily.